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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2

Alexia Martínez de Paz, Leila Khajavi, Hélène Martin, Rafael Claveria-Gimeno, Susanne tom Dieck, Manjinder S. Cheema, Jose V. Sanchez-Mut, Malgorzata M. Moksa, Annaick Carles, Nick I. Brodie, Taimoor I. Sheikh, Melissa E. Freeman, Evgeniy V. Petrotchenko, Christoph H. Borchers, Erin M. Schuman, Matthias Zytnicki, Adrian Velazquez-Campoy, Olga Abian, Martin Hirst, Manel Esteller, John B. Vincent, Cécile E. Malnou, Juan Ausió
doi: https://doi.org/10.1101/392092
Alexia Martínez de Paz
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada.
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Leila Khajavi
2Unité de Mathématiques et Informatique Appliquées, Toulouse INRA, Auzeville BP 52627, 31326 Castanet-Tolosan cedex, France.
3Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
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Hélène Martin
3Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
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Rafael Claveria-Gimeno
4Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain.
5Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain.
6Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain.
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Susanne tom Dieck
7Max-Planck-Institute for Brain Research, Synaptic Plasticity Department, Frankfurt/Main, Germany.
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Manjinder S. Cheema
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada.
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Jose V. Sanchez-Mut
8School of Life Sciences, École Polytechnique Fédérale de Lausanne, Brain Mind Institute, Lausanne, CH-1015, Switzerland.
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Malgorzata M. Moksa
9Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
10Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
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Annaick Carles
9Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
10Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
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Nick I. Brodie
11University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, British Columbia V8Z7X8, Canada.
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Taimoor I. Sheikh
12Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.
13Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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Melissa E. Freeman
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada.
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Evgeniy V. Petrotchenko
11University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, British Columbia V8Z7X8, Canada.
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Christoph H. Borchers
11University of Victoria-Genome British Columbia Proteomics Centre, Vancouver Island Technology Park, #3101-4464 Markham Street, Victoria, British Columbia V8Z7X8, Canada.
14Department of Biochemistry and Microbiology, University of Victoria, Room 270d, Petch Building, 3800 Finnerty Road, Victoria, British Columbia V8P 5C2, Canada.
15Gerald Bronfman Department of Oncology, Jewish General Hospital, Suite 720, 5100 de Maisonneuve Boulevard West, Montreal, Quebec H4A 3T2, Canada.
16Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Sainte-Catherine Road, Montreal, Quebec H3T 1E2, Canada.
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Erin M. Schuman
7Max-Planck-Institute for Brain Research, Synaptic Plasticity Department, Frankfurt/Main, Germany.
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Matthias Zytnicki
2Unité de Mathématiques et Informatique Appliquées, Toulouse INRA, Auzeville BP 52627, 31326 Castanet-Tolosan cedex, France.
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Adrian Velazquez-Campoy
4Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain.
5Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain.
17Department of Biochemistry and Molecular and Cell Biology, Universidad de Zaragoza, 50009 Zaragoza, Spain.
18Fundación ARAID, Government of Aragon, 50018 Zaragoza, Spain.
19Biomedical Reseach Networking Centre for Liver and Digestive Diseases (CIBERehd), Madrid, Spain.
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Olga Abian
4Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI and GBsC-CSC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain.
5Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain.
6Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain.
17Department of Biochemistry and Molecular and Cell Biology, Universidad de Zaragoza, 50009 Zaragoza, Spain.
19Biomedical Reseach Networking Centre for Liver and Digestive Diseases (CIBERehd), Madrid, Spain.
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Martin Hirst
8School of Life Sciences, École Polytechnique Fédérale de Lausanne, Brain Mind Institute, Lausanne, CH-1015, Switzerland.
9Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
20Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada V5Z 1L3.
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Manel Esteller
21Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avinguda Gran Vía de L’Hospitalet 199-203. L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
22Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
23Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
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John B. Vincent
12Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.
13Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.
24Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
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Cécile E. Malnou
3Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
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Juan Ausió
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, V8W 3P6, Canada.
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  • For correspondence: jausio@uvic.ca
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Abstract

MeCP2 – a chromatin-binding protein associated with Rett syndrome – has two main isoforms, MeCP2-E1 and MeCP2-E2, with 96% amino acid identity differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored. Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl binding domain (MBD) to interact with DNA as well as influencing the turnover rates, binding dynamics, response to nuclear depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes. Our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.

Significance Whether the two E1 and E2 isoforms of MeCP2 have different structural and/or functional implications has been highly controversial and is not well known. Here we show that the relatively short N-terminal sequence variation between the two isoforms impinges them with an important DNA binding difference. Moreover, MeCP2-E1 and E2 exhibit a different cellular dynamic behavior and have some distinctive interacting partners. In addition, while sharing genome occupancy they specifically bind to several distinctive genes.

AUTHOR CONTRIBUTIONS

AMdP and JA designed and wrote the paper. AMdP, MSC, HM, CM, MEF and TIS performed the biochemical/molecular biology experiments, RC-G, OA and AV-C designed and performed the calorimetry and spectroscopy experiments, MMM provided assistance with construction of the ChIP libraries, NIB and EVP carried out the proteomic analyses, LK, MZ and AC conducted the bioinformatic analyses of the CHIP-seq data, STD and EMS performed the immunofluorescence, JVS-M, MZ, AV-C, JBV, MH, ME and CM contributed to the writing and discussion of specific sections of the manuscript.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 17, 2018.
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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Alexia Martínez de Paz, Leila Khajavi, Hélène Martin, Rafael Claveria-Gimeno, Susanne tom Dieck, Manjinder S. Cheema, Jose V. Sanchez-Mut, Malgorzata M. Moksa, Annaick Carles, Nick I. Brodie, Taimoor I. Sheikh, Melissa E. Freeman, Evgeniy V. Petrotchenko, Christoph H. Borchers, Erin M. Schuman, Matthias Zytnicki, Adrian Velazquez-Campoy, Olga Abian, Martin Hirst, Manel Esteller, John B. Vincent, Cécile E. Malnou, Juan Ausió
bioRxiv 392092; doi: https://doi.org/10.1101/392092
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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Alexia Martínez de Paz, Leila Khajavi, Hélène Martin, Rafael Claveria-Gimeno, Susanne tom Dieck, Manjinder S. Cheema, Jose V. Sanchez-Mut, Malgorzata M. Moksa, Annaick Carles, Nick I. Brodie, Taimoor I. Sheikh, Melissa E. Freeman, Evgeniy V. Petrotchenko, Christoph H. Borchers, Erin M. Schuman, Matthias Zytnicki, Adrian Velazquez-Campoy, Olga Abian, Martin Hirst, Manel Esteller, John B. Vincent, Cécile E. Malnou, Juan Ausió
bioRxiv 392092; doi: https://doi.org/10.1101/392092

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